Makova K D, Ramsay M, Jenkins T, Li W H
Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637, USA.
Genetics. 2001 Jul;158(3):1253-68. doi: 10.1093/genetics/158.3.1253.
An approximately 6.6-kb region located upstream from the melanocortin 1 receptor (MC1R) gene and containing its promoter was sequenced in 54 humans (18 Africans, 18 Asians, and 18 Europeans) and in one chimpanzee, gorilla, and orangutan. Seventy-six polymorphic sites were found among the human sequences and the average nucleotide diversity (pi) was 0.141%, one of the highest among all studies of nuclear sequence variation in humans. Opposite to the pattern observed in the MC1R coding region, in the present region pi is highest in Africans (0.136%) compared to Asians (0.116%) and Europeans (0.122%). The distributions of pi, theta, and Fu and Li's F-statistic are nonuniform along the sequence and among continents. The pattern of genetic variation is consistent with a population expansion in Africans. We also suggest a possible phase of population size reduction in non-Africans and purifying selection acting in the middle subregion and parts of the 5' subregion in Africans. We hypothesize diversifying selection acting on some sites in the 5' and 3' subregions or in the MC1R coding region in Asians and Europeans, though we cannot reject the possibility of relaxation of functional constraints in the MC1R gene in Asians and Europeans. The mutation rate in the sequenced region is 1.65 x 10(-9) per site per year. The age of the most recent common ancestor for this region is similar to that for the other long noncoding regions studied to date, providing evidence for ancient gene genealogies. Our population screening and phylogenetic footprinting suggest potentially important sites for the MC1R promoter function.
对位于黑皮质素1受体（MC1R）基因上游并包含其启动子的一个约6.6千碱基区域，在54名人类（18名非洲人、18名亚洲人和18名欧洲人）以及一只黑猩猩、一只大猩猩和一只猩猩中进行了测序。在人类序列中发现了76个多态性位点，平均核苷酸多样性（π）为0.141%，是人类核序列变异所有研究中最高的之一。与在MC1R编码区观察到的模式相反，在本区域中，非洲人的π最高（0.136%），而亚洲人（0.116%）和欧洲人（0.122%）的π较低。π、θ以及傅和李的F统计量的分布在序列中以及各大洲之间是不均匀的。遗传变异模式与非洲人群的扩张一致。我们还提出，非非洲人群可能存在种群数量减少的阶段，以及在非洲人群的中间子区域和5'子区域的部分存在纯化选择。我们假设在亚洲人和欧洲人的5'和3'子区域或MC1R编码区的某些位点存在多样化选择，尽管我们不能排除亚洲人和欧洲人MCXR基因中功能限制放松的可能性。测序区域的突变率为每年每个位点1.65×10⁻⁹。该区域最近共同祖先的年代与迄今为止研究的其他长非编码区域相似，为古老的基因谱系提供了证据。我们的群体筛查和系统发育足迹分析表明了MC1R启动子功能潜在的重要位点。
